Data from Mutant IDH1 Expression Drives <i>TERT</i> Promoter Reactivation as Part of the Cellular Transformation Process

Abstract

<div>Abstract<p>Mutations in the isocitrate dehydrogenase gene <i>IDH1</i> are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the <i>ATRX</i> gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1<sup>mut</sup>) genes as they progressed through their lifespan. IDH1<sup>mut</sup> expression promoted 2HG production and altered histone methylation within 20 population doublings (PD) but had no effect on telomerase expression or telomere length. Accordingly, cells expressing either IDH1<sup>WT</sup> or IDH1<sup>mut</sup> entered a telomere-induced crisis at PD 70. In contrast, only IDH1<sup>mut</sup> cells emerged from crisis, grew indefinitely in culture, and formed colonies in soft agar and tumors <i>in vivo</i>. Clonal populations of postcrisis IDH1<sup>mut</sup> cells displayed shared genetic alterations, but no mutations in ATRX or the TERT promoter were detected. Instead, these cells reactivated telomerase and stabilized their telomeres in association with increased histone lysine methylation (H3K4me3) and c-Myc/Max binding at the TERT promoter. Overall, these results show that although IDH1<sup>mut</sup> does not create or select for ATRX or TERT promoter mutations, it can indirectly reactivate TERT, and in doing so contribute to astrocytic immortalization and transformation. <i>Cancer Res; 76(22); 6680–9. ©2016 AACR</i>.</p></div>